KR100517399B1 - Solid pharmaceutical compositions containing miltefosine for oral administration in the treatment of leishmaniasis - Google Patents

Abstract

The present invention provides a novel solid pharmaceutical composition containing hexadecylphosphocholine (miltefosine) for oral administration in the treatment of leshmaniasis, a method for preparing the pharmaceutical composition, the pharmaceutical composition in the treatment of leshmaniasis. A method of administration for oral administration of and a combination comprising said solid pharmaceutical composition, an antiemetic agent and / or an antidiarrheal agent.

Description

Solid pharmaceutical compositions containing miltefosine for oral administration in the treatment of leishmaniasis

I. Examples of Oral Solid Pharmaceutical Formulations According to the Invention

Example 1 Hard Gelatin Capsule (Content: Miltefosine 10mg)

100 g of hexadecylphosphocholine, 808.50 g of lactose, 448.50 g of microcrystalline cellulose, 26 g of talc and 13 g of highly dispersed silicon dioxide were filtered through a sieve having a mesh number of 0.8 mm and then homogenized in a suitable mixer for 30 minutes. Then 4 g magnesium stearate (0.8 mm sieve) are added and the components are further mixed for 5 minutes. The resulting mixture is filled in 140 mg portions into 50 mg hard gelatine capsules by known methods using a suitable encapsulator. Each capsule obtained (total weight: 190 mg) contained 10 mg of hexadecylphosphocholine. The ratio of hexadecylphosphocholine: rheology-modulator / surfactant: filler in the fill mixture is 1: 0.4: 12.4 (parts by weight).

Example 2: Hard Gelatin Capsule (Content: Miltefosine 50mg)

258 g of hexadecylphosphocholine, 430 g of lactose, 241 g of microcrystalline cellulose, 14 g of talc, 7 g of highly dispersed silicon dioxide and 2 g of magnesium stearate are mixed according to the method described in Example 1. The filling mixture thus obtained is charged to a volume of 185 mg in a 59 mg weight hard gelatin capsule by known methods using a suitable encapsulator. Each capsule obtained (total weight: 244 mg) contained 50 mg of hexadecylphosphocholine. The ratio of hexadecylphosphocholine: flow-controlling agent and lubricant: filler in the fill mixture is 1: 0.09: 2.6 (parts by weight).

Example 3: Hard Gelatin Capsule (Content: Miltefosine 100mg)

1000 g hexadecylphosphocholine, 584 g lactose, 345 g microcrystalline cellulose, 50 g talc, 15 g highly dispersed silicon dioxide and 6 g magnesium stearate are mixed according to the method described in Example 1. The filling mixture thus obtained is charged in a amount of 200 mg into 76 mg weight hard gelatin capsules by known methods using a suitable encapsulator. Each capsule obtained (total weight: 276 mg) contained 100 mg of hexadecylphosphocholine. The ratio of hexadecylphosphocholine: rheology-modulator: filler in the fill mixture is 1: 0.07: 0.9 (parts by weight).

Example 4 Hard Gelatin Capsule (Content: Miltefosine 150mg)

150 g hexadecylphosphocholine, 30 g lactose, 15 g microcrystalline cellulose, 3 g talc, 2 g highly dispersed silicon dioxide and 1 g magnesium stearate are mixed according to the method described in Example 1. The filling mixture thus obtained is filled in 201 mg portions into 76 mg weight gelatin hard capsules by known methods using a suitable encapsulator. Each capsule obtained (total weight: 277 mg) contained 150 mg of hexadecylphosphocholine. The ratio of hexadecylphosphocholine: rheology-modifier: filler in the fill mixture is 1: 0.04: 0.3 (parts by weight).

Example 5 Hard Gelatin Capsule (Content: Miltefosine 200 mg)

200 g of hexadecylphosphocholine, 80 g of lactose, 50 g of microcrystalline cellulose, 4 g of talc, 5 g of highly dispersed silicon dioxide and 10 g of magnesium stearate are mixed according to the method described in Example 1. The filling mixture thus obtained is charged in an amount of 349 mg into a 97 mg weight hard gelatin capsule by a known method using a suitable encapsulator. Each capsule obtained has a total weight of 446 mg and contains 200 mg of hexadecylphosphocholine. The ratio of hexadecylphosphocholine: rheology-modulator: filler in the fill mixture is 1: 0.095: 0.65 (parts by weight).

Example 6: Hard Gelatin Capsule (Content: Miltefosine 250mg)

250 g hexadecylphosphocholine, 80 g lactose, 50 g microcrystalline cellulose, 5 g talc, 5 g highly dispersed silicon dioxide and 15 g magnesium stearate are mixed according to the method described in Example 1. The filling mixture thus obtained is charged in an amount of 405 mg into a 97 mg weight hard gelatin capsule by known methods using a suitable encapsulator. Each capsule obtained has a total weight of 502 mg and contains 250 mg of hexadecylphosphocholine. The ratio of hexadecylphosphocholine: rheology-modulator: filler in the fill mixture is 1: 0.1: 0.52 (parts by weight).

Example 7: Tablet (Content: 250 mg of hexadecylphosphocholine)

50 g of hexadecylphosphocholine, 24.25 g of microcrystalline cellulose and anhydrous dicalcium phosphate are sieved and mixed. 3.75 g of magnesium stearate is sieved and added to the mixture. Then the mixture is mixed again. The resulting mixture is compressed into tablets weighing 500 mg each. One tablet contains 250 mg of hexadecylphosphocholine. The ratio of hexadecylphosphocholine: rheology-modulator / surfactant: filler in the tablet is 1: 0.07: 0.925 (parts by weight).

Example 8: Tablet (Content: Hexadecylphosphocholine 30 mg)

23 g hexadecylphosphocholine, 23 g microcrystalline cellulose and 52 g spray-dried lactose are sieved and mixed. 1 g colloidal silicon dioxide and 1 g magnesium stearate are added. Then the mixture is mixed again. The resulting mixture is compressed into tablets weighing 130.5 mg each. One tablet contains 30 mg of hexadecylphosphocholine. The ratio of hexadecylphosphocholine: rheology-modulator / surfactant: filler in the tablet is 1: 0.087: 0.31 (parts by weight).

Example 9 effervescent tablets and effervescent blends (content: hexadecylphosphocholine 250 mg)

1700 g of granular sodium bicarbonate is placed in an oven and heated at 100 ° C. for 60 minutes. After cooling to room temperature, the converted bicarbonate is mixed with 160 g of granular monobasic calcium phosphate, 1030 g of granular citric anhydride, 100 g of talc and 50 g of magnesium stearate. 300 g of hexadecylphosphocholine is added to the resulting mixture and mixed for 10 minutes. The resulting foam blend is compressed into tablets weighing 278 mg each. One effervescent tablet contains 250 mg of hexadecylphosphocholine. The ratio of hexadecylphosphocholine: rheology-modulator / surfactant: filler in the tablet is 1: 0.50: 0.53 (parts by weight).

Alternatively, the foamed blend may be charged into a sachet in an amount of 278 mg to obtain a foamed blend.

Example 10 effervescent tablets and effervescent blends (content: hexadecylphosphocholine 50 mg)

1600 g of granular sodium bicarbonate is placed in an oven and heated at 100 ° C. for 60 minutes. After cooling to room temperature, the converted bicarbonate is mixed with 150 g of granular monobasic calcium phosphate, 900 g of granular anhydrous citric acid, 80 g of talc and 30 g of magnesium stearate. To the resulting mixture is added 200 g of hexadecylphosphocholine and mixed for 10 minutes. The resulting mixture is compressed into tablets weighing 740 mg each. One effervescent tablet contains 50 mg of hexadecylphosphocholine. The ratio of hexadecylphosphocholine: rheology-modulator / surfactant: filler in the tablet is 1: 0.55: 0.75 (parts by weight).

Alternatively, the foamed blend may be charged into a sachet in an amount of 740 mg to obtain a foamed blend.

Example 11: Drinkable Blend (Sachets) (Content: Hexadecylphosphocholine 50 mg)

5 g hexadecylphosphocholine, 308 g lactose, 280 g microcrystalline cellulose, 5 g saccharin and 2 g colloidal silicon dioxide are mixed. Fill the blend into the sachet. One sachet weighs 6 g and contains 50 mg of hexadecylphosphocholine. The ratio of hexadecylphosphocholine: rheology-modulator / surfactant: filler in the blend is 1: 0.4: 117.5 (parts by weight).

Example 12 Drinkable Blend (Sachets) (Content: Hexadecylphosphocholine 100 mg)

10 g hexadecylphosphocholine, 200 g lactose, 250 g microcrystalline cellulose, 7 g saccharin and 3 g colloidal silicon dioxide are mixed. Fill the blend into the sachet. One sachet weighs 4.7 g and contains 100 mg of hexadecylphosphocholine. The ratio of hexadecylphosphocholine: rheology-modulator / surfactant: filler in the blend is 1: 0.3: 45 (parts by weight).

Example 13: Drinkable Blend (Sachets) (Content: Hexadecylphosphocholine 200 mg)

20 g of hexadecylphosphocholine, 306 g of lactose, 403 g of microcrystalline cellulose, 5 g of saccharin and 6 g of colloidal silicon dioxide are mixed. Fill the blend into the sachet. One sachet weighs 7.4 g and contains 200 mg of hexadecylphosphocholine. The ratio of hexadecylphosphocholine: rheology-modulator / surfactant: filler in the blend is 1: 0.3: 35.5 (parts by weight).

II. Clinical Study Results in the Treatment of Leishmaniasis Orally Administered Capsules According to the Invention

In the following, the abbreviation means:

1 qod = once every other day;

BID qod = dose every other day;

BID = twice daily;

TID = 3 times daily;

QID = 4 doses per day.

Miltefosine (MILT, hexadecylphosphocholine, ASTA Medica), an anti-neoplastic alkylphospholipid, is active in experimental visceral leshumaniasis (VL). To test oral MILT in human VL, 30 male Indian patients from Bihar exhibiting aspirate-positive VL (age is> 14 years old; 18 of 30 patients were treated with antimony (Sb) insufficiency], divided into 6 groups (groups A to F) of 5 each, and the capsules according to Example 1 were treated for 28 days with increasing doses by oral administration. (A) 50 mg once qod (qod = q uanity every o ther d ay), (B) 50 mg BID qod (BID = 1 twice per day) followed by 50 mg daily (C) BID (100 mg / Days), (D) TID (150 mg / day), (E) QID (200 mg / day) and (F) 5 times per day (250 mg / day).

Sixteen patients had no fever on day 7. Results were obtained in 30 patients on day 14: 25 had no fever, 25 had reduced spleen size, 28 had negative spleen puncture fluid (apparent parasitological treatment); Twenty-one of the thirty patients had all three reactions and were regarded as obvious treatments. One patient in group F died on day 21 (drug discontinuation on day 19) with severe vomiting and diarrhea (drug- or concomitant gastroenteritis-related possibility), dehydration and renal failure. Mild vomiting and diarrhea lasting 3 to 7 days were seen in most patients in Groups B through E. One of Group E and three or more of Group F were excluded due to vomiting on days 7, 7, 8 and 10. Therefore, 200 mg / day was the maximum acceptable daily dose. There was no hematologic toxicity. One patient in group F had increased liver transaminase (degradation). On day 28, 29 of 29 (100%) patients were clearly treated, including 4 patients treated less than 10 days, with no further treatment. Within 6 months, 7 of 29 apparently treated (3 of A-5, 3 of B-5, 1 of D-5) recurred; Six of seven relapse patients were in the low dose qod-administered groups (A, B). Within 6 months, obvious treatment (no recurrence, bone marrow puncture with no parasites) was found in 21 of 26 patients (2 out of A-5, 2 out of B-5, 5 out of C-5, and D-5). 4 patients, 5 of E-5)), one patient was still under investigation, and 14 of the first 21 patients who received constant treatment had no prior treatment with antimony.

The above results demonstrate that the solid pharmaceutical composition and the method of administration according to the present invention are effective in the treatment of leschmania by oral administration. Obvious treatment was observed even in patients with the problem of increasing antimony-nonreactive visceral infections.

The present invention provides a novel solid pharmaceutical composition containing hexadecylphosphocholine (miltefosine) for oral administration in the treatment of leshmaniasis, a method for preparing the pharmaceutical composition, the pharmaceutical composition in the treatment of leshmaniasis. It relates to a method of administration for oral administration of and finally to a combination comprising said solid pharmaceutical composition, antiemetic and / or anti-branching agent.

Leshumaniasis refers to a variety of tropical diseases caused by flagellar reptiles of the genus Leshumania. Symptoms of reshumaniasis may be visceral (kala-azar), mucosal skin (American Leshumaniasis) or skin (Aleppo boil or diffuse skin reshumaniasis). The incubation period is weeks or months. Untreated, very high mortality rates are observed, especially in Cala-Azar and American Leshumania.

In the prior art prior to the present invention there was no medicament that could be used for oral treatment of leschmania. Agents known from standard therapies for the treatment of reshumania, i.e. pentavalent antimony compounds (e.g. sodium stybogluconate) and aromatic diamidines, due to their high toxicity, not only cause serious side effects but also increase the risk of infection And had to be administered by intravenous injection.

Leshumania is a parasitic disease that commonly occurs in regions of extreme tropical climates where medical care is difficult due to insufficient transport routes. Therefore, all medications containing milteposine for treating reshumania must take into account harsh environmental conditions.

The availability of milephosine in oral and topical therapies for leshumaniasis is described in Eibl et al. German unexamined patent application No. P41 32 344, filed Sep. 27, 1991] for the first time.

Miltefosine is obtainable in anhydrous form as a crystalline plate having a defined melting point of 200 ° C. or higher, but is difficult to handle due to its high hygroscopicity. Incorporation of water molecules can lead to weight gain of up to 30% by weight, lowering of melting point and aggregation and agglomeration of crystals. Water-containing miltefosins exhibit insufficient processability for further processing into solid pharmaceutical compositions such as tablets, capsules or sachets. In particular, the fluidity of the water-containing miltopesin is insufficient. However, satisfactory fluidity is one of the essential prerequisites for producing solid pharmaceutical compositions on an industrial scale.

In addition, anhydrous miltefosine exhibits a significant electrostatic charge tendency, especially when stirred in the anhydrous state. Electrostatically charged Miltefosine also exhibits insufficient fluidity in further processing into the solid pharmaceutical composition. Moreover, all electrostatic charges require considerable care because they carry the risk of explosion and damage to sensitive electronic components.

In an attempt to overcome the above-mentioned problems in the preparation of a solid pharmaceutical composition containing miltefosine, Eibl et al. Reported that silicon dioxide was evaporated to dry the suspension of 1 part by weight of silicon dioxide in a solution containing 1 part by weight of miltefosine. It has been proposed to coat Miltefosine on the surface of the particles. The resulting solid dispersions proposed by Able et al. Exhibit sufficient fluidity to fill into capsules, at least as far as laboratory scale is concerned. However, high volatility and non-flammable (due to electrostatic charge) solvents must be used in the process as described by Able et al. Given all practical purposes, only two solvents are available at the level of the art that meet this need, namely methylene chloride and chloroform. However, halogenated hydrocarbons, especially chloroform, are classified as toxic and carcinogenic compounds. In addition, halogenated hydrocarbons accumulate in fatty tissue and are slowly metabolized. Thus, the development of solid pharmaceutical compositions as disclosed by Able et al. Is unlikely to be approved by a formal health agency, as far as at least part of the food chain is concerned with humans and animals.

As discussed above, solid pharmaceutical compositions for oral administration in the treatment of leshmaniasis have long been required. It is an object of the present invention to solve this problem.

Surprisingly unexpectedly, one or more rheology-modulators and / or lubricants selected from the group consisting of hexadecylphosphocholine, and highly dispersed silicon dioxide, talc, magnesium stearate and mixtures thereof, and lactose according to one embodiment of the present invention It has now been found that the above-mentioned problems can be solved by simply physically mixing one or more fillers selected from the group consisting of microcrystalline cellulose and mixtures thereof.

The subject matter of the present invention is novel and unobvious from the prior art, since it no longer requires carrier particles or granulation solvents to obtain a solid pharmaceutical composition with sufficient fluidity containing miltefosine. According to the invention, by simply physically mixing miltefosine, rheology-modulators and / or lubricants and one or more fillers, to provide a solid pharmaceutical mixture having sufficient fluidity for further processing, for example into capsules, tablets or sachets. can do.

In contrast, those skilled in the art would have attempted to achieve the desired fluidity by granulation methods or solid dispersion methods using granulation solvents other than water (due to hygroscopicity of miltefosine), according to the teachings of Able et al. In the latter case, excess silica gel is required.

Accordingly, the subject matter of the present invention is novel and advances over the prior art.

In a preferred embodiment, the solid pharmaceutical composition according to the invention can be filled into capsules, preferably hard gelatin capsules, or compressed into tablets or effervescent tablets, or filled into sachets as drinkable mixtures or effervescent mixtures. You can.

The content of miltopesin per dosage unit is in the range of 10 to 800 mg, preferably 10 to 500 mg, more preferably 50 to 250 mg. The most preferred content is in the range of 50 to 150 mg.

Suitable flow-controlling agents are, for example. Lubricants include, for example, other stearates such as magnesium stearate or calcium stearate, D, L-leucine, talc, stearic acid, lauric acid, polyglycol (average molecular weight 3000 to 35000), fatty alcohols or waxes. Can be used. The preferred ratio of miltefosine to the rheology-modulating agent and / or lubricant is 0.01 to 0.6 parts by weight of the rheology-modifying agent relative to 1 part by weight of milteposine.

Anti-adhesives are, for example, glycols, starches, talc, talc siliconisumum, aluminum stearate, stearic acid, magnesium stearate, calcium stearate or D, L-leucine.

Suitable flow-controlling agents, lubricants and antiadhesives are described in the literature: W.A. Ritschel, DIE TABLETTE, Editio Cantor Verlag, page 125, 1st edition 1996; Sucker, Fuchs, Speiser, PHARMAZEUTISCHE TECHNOLOGIE, g. Thieme Verlag, Stuttgart, pages 334 to 336, 1st edition 1978; Munzel, Buchi, Schultz, GALENISCHES PRAKTIKUM, Wissenschaftliche Verlagsanstalt, Stuttgart, page 731, 1st edition, 1959: R. Voigt, LEHRBUCH DER PHARMAZEUTISCHEN TECHNOLOGIE, 4th edition, Verlag Chemie, Weinheim, page 195, 1st edition 1982; P.H. List, ARZNEIMITTELLEHRE, Wissenschaftliche Verlagsanstalt, Stuttgart, page 86, 1st edition 1976.

Solid pharmaceutical compositions according to the present invention may contain a binder such as gelatin, cellulose, cellulose ethers, amylose, dextrose, polyglycol, tragacanth, pectin, alginate, polyvinylpyrrolidone.

Solid pharmaceutical compositions according to the invention also include, for example, starch (eg corn starch), modified starch (eg sodium starch glycolate, starch 1500), pectin, betonite, cellulose, cellulose derivatives (eg carboxy) Methyl cellulose), alginate, polyvinyl pyrrolidone, ultraamylopectin, crosslinked polyvinylpyrrolidone or crosslinked carboxymethyl cellulose (Ac-Di-Sol / FMC).

Suitable fillers are, for example, lactose (eg spray-dried lactose), glucose, fructose, calcium phosphate, calcium sulfate, calcium carbonate, starch, modified starch, sugar alcohols such as sorbitol or mannitol, cellulose derivatives , Saccharose, microcrystalline cellulose and mixtures thereof. The preferred ratio of miltefosine to the filler is 0.1 to 120 parts by weight of the filler relative to 1 part by weight of miltefosine.

According to a further aspect of the invention,

(a) mixing miltefosine, rheology-modulating agent and filler, optionally with additional auxiliaries, to obtain a pharmaceutical composition with sufficient fluidity, and

(b) a method for the preparation of a pharmaceutical composition according to the invention which comprises the step of filling the obtained mixture into capsules or sachets or compressing the obtained mixture into tablets.

The preparation of oral pharmaceutical compositions according to the invention comprises mixing or homogenizing Miltefosine at a temperature of 20-120 ° C. with conventional physiologically acceptable fillers, carriers, diluents and / or auxiliary substances, In order to prepare a formulation containing 10 to 800 mg of Miltefosine in one dosage unit, the obtained mixture is poured into a hollow cell of a suitable size, filled into a capsule of a suitable size, or granulated It is then compressed into tablets and optionally carried out by the addition of further conventional auxiliary substances. Active substances can be prepared, for example, by mixing with one or more of the following auxiliary substances: starch, cellulose, lactose, formalin-casein, modified starch, magnesium stearate, calcium hydrogen phosphate, highly disperse silicic acid, talc and phenoxy Siethanol. The resulting mixture, if desired, contains, for example, gelatin, starch, polyvinyl pyrrolidone, vinylpyrrolidone-vinyl acetate copolyheadate or / and polyoxyethylene consuming monooleate as constituents. Granulate with an aqueous solution and the granules are homogenized, optionally with one or more of the aforementioned auxiliary substances. The mixture can then be compressed into tablets or filled into capsules, each tablet or capsule containing 10 to 800 mg of milteosin in one dosage unit.

The preparation of capsules and tablets is carried out, for example, at 15 ° C to 26 ° C, preferably at 18 ° C to 22 ° C. It is preferable that the relative humidity of a manufacturing room does not exceed 40%.

The preparation of the solid pharmaceutical composition according to the invention is carried out in a conventional manner, and also conventional conventional pharmaceutical auxiliary substances and other conventional carriers and diluents may be used.

According to the invention, the process for the preparation of the pharmaceutical composition may further comprise the step of granulating the composition having sufficient fluidity obtained according to step (a) by a method known before step (b). Granulation can be performed according to methods known in the art (Hagers Handbuch der pharmazeutischen Praxis, 5th edition, Springer Verlag, 1991, pages 722-742). The mixture can be melted using a liquid and, if necessary, the wet compound can then be filtered through a filter. Additional processing steps are drying, screening, mixing with additional excipients, and filling into sachets or capsules, or compacting into tablets. In addition, the mixture may be prepared or extruded according to the prior art to obtain granules.

Carriers and excipients may be contemplated as presented or cited in the following literature as auxiliary substances in pharmacy, cosmetology and related fields: "Ullmanns Encyklopadie der technischen Chemie", Volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 et seq .; H.v. Czetsch-Lindenwald, "Hilfsstoffe fur Pharmazie und angrenzende Gebiete"; Pharm. Ind. issue 2 (1961), page 72 et seq .; Dr. H. P. Fiedler, "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete" cantor KG, Aulendorf in Wurttemberg 1981.

Examples include natural sugars such as gelatin, raw sugar or lactose, lecithin, pectin starch (e.g. corn starch), cyclodextrin and cyclodextrin derivatives, polyvinyl pyrrolidone, polyvinyl acetate, gelatin, gum arabic, alginic acid, Tylose, talc, lycopodium, silica gel (e.g. colloidal silica gel), cellulose, cellulose derivatives (e.g. cellulose hydroxy groups are partially etherified by lower saturated aliphatic alcohols and / or lower saturated aliphatic oxyalcohols Cellulose ethers such as methyloxypropyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate); In addition to fatty acids, magnesium, calcium or aluminum salts of fatty acids having 12 to 22 carbon atoms, in particular saturated salts such as stearates, emulsifiers, fats and oils, especially vegetable fats such as peanut oil, castor oil, olive oil, Sesame oil, cottonseed oil, corn oil, malt oil, sunflower seed oil, cod liver oil: each hydrogenated); Mono-, di- and triglycerides and mixtures thereof of saturated fatty acids C ₁₂ H ₂₄ O ₂ to C ₁₈ H ₃₆ O ₂ , polyglycols such as pharmaceutically acceptable monohydric or polyhydric alcohols and polyethylene glycols and derivatives thereof, optionally Aliphatic saturated or unsaturated fatty acids (2 to 22 carbons) with monohydric aliphatic alcohols (1-20 carbon atoms) that can be etherified or polyhydric alcohols such as glycols, glycerin, diethylene glycol, pentaerythritol, sorbitol, mannitol and the like Esters of atoms, in particular 10 to 18 carbon atoms), esters of citric acid with primary alcohols, acetic acid, benzylbenzoate, dioxalane, glycerin formals, tetrahydrofurfuryl alcohol, poly with C ₁ -C ₁₂ alcohols Glycol ether, dimethylacetamide, lactamide, lactate, ethyl carbonate, silicon (especially medium-viscosity polydimethylsiloxane), calcium carbonate, carbon There are sodium and calcium phosphate, sodium phosphate, magnesium carbonate and the like.

Other excipients that can be used include disintegrating agents (disintegrants) such as crosslinked polyvinylpyrrolidone, sodium carboxymethyl starch, sodium carboxymethyl cellulose or microcrystalline cellulose.

Powders are prepared by the following methods: Miltefosine, one or more rheology-modulators and / or lubricants, one or more fillers and any flavoring and / or sweetening agents are mixed and filled into sachets of suitable dosage units. In use, all or part of the contents of the bag is swallowed by stirring in water or fruit juice. This method facilitates the application of all levels of dosage by the oral route.

To prepare effervescent tablets or effervescent blends, miltefosine, one or more rheology-controlling agents and / or lubricants, one or more fillers are mixed in a conventional manner with carbonate or acid components, optionally with flavors, lost acid components, or After addition of carbonates as well as other flow-controlling agents and lubricants, the resulting mixture is compressed into tablets or filled into sachets. Likewise, administration is carried out by dissolving the tablet or mixture in water.

Solid pharmaceutical compositions according to the invention may also further contain flavoring, sweetening and / or aromatic substances.

Aromatic substances include pineapples, apples, apricots, raspberries, cherries, cola, oranges, tropical fruits, lemons, grapefruit, vanilla and chocolate. The following materials can be used as sweeteners: saccharin and its sodium salt, cyclic acid and its sodium salt, ammonium glycyrizinate, fructose, xylitol, sorbitol, mannitol, aspartan, acesulfame-K.

Effervescent powders or chewing or effervescent tablets are prepared using conventional methods as described in Sucker, Fuchs, and Speiser (edit.), Pharmazeutische Technologie, Thieme Verlag, Stuttgart. Preparation (all steps except drying) is carried out, for example, at a temperature of 10 ° C. to 80 ° C., preferably 18 ° C. to 50 ° C., in particular 20 ° C. to 30 ° C.

The preparation of miltefosine is described in detail in the examples for hexadecylphosphocholine as described in German Unexamined Patent Application P41 32 344. Another method for preparing and purifying Miltefosine is German unexamined patent application (DE-A 27 52 125, DE-A 36 41 379, DE-A 36 41 491, DE-A 40 13 632, DE-A 36 41 377 And these cited documents or previous patent applications or patent specifications are incorporated herein by reference.

According to a further aspect of the present invention there is provided a method of administration for the treatment of reshumania in humans by oral administration of the pharmaceutical composition according to the invention.

In a preferred embodiment of the invention, the following methods of administration for the treatment of human reshumaniasis by oral administration are suitable:

Total daily dose: 10 to 250 mg, preferably 50 to 150 mg of the active ingredient Miltefosine.

Daily single dose or multiple daily doses: Preferably, a total daily dose of 10-50 mg of active ingredient is administered as a single daily dose; Doses of 50 to 250 mg of the active ingredient, preferably 50 to 150 mg of the active ingredient, are multiple daily doses, preferably twice daily (total daily dose: 100 mg active ingredient) or three times daily (Total Daily Dose: 150 mg Active Ingredient). In consideration of patient compliance, the daily dose divided into 4 to 5 is generally considered as the upper limit. However, for treatment reasons, one to five divided daily doses may be applied.

In a preferred embodiment, multiple daily doses are administered in the same amount (eg, 100 mg / day active ingredient = 2 × 50 mg active ingredient / day or 150 mg active ingredient / day = 3 × 50 mg active ingredient / day).

Duration of treatment: 2-6 weeks, preferably 4 weeks.

According to a further aspect of the present invention there is provided a method of administration for the treatment of reshumaniaosis in mammals other than humans by oral administration of the pharmaceutical composition according to the invention.

All mammals, for example dogs, all rodents and small pets such as hamsters can be treated by the present invention. The treatment may be performed in the animal's natural environment or in a selected environment, such as an animal hospital or veterinary office, but the former is preferred. All Leshumania species, in particular Leshumania adult and Leshumania larvae, can be treated by the methods of administration of the present invention. According to the method of administration of the invention, the total daily dosage in the treatment by oral administration is 1-15 mg of Miltefosine active ingredient per kg body weight of the animal (mg / kg active ingredient). In a preferred embodiment, treatment starts with an initial total single dose (loading dose) in the range of 3 to 15, preferably 5 to 10 mg active ingredient / kg, followed by 1 to 10, preferably 3 to 5 mg active ingredient Continue the total daily dose (maintenance dose) in the / kg range. The treatment period is 2 to 8, preferably 4 to 5 weeks.

According to a further aspect of the present invention there is provided a combination of the pharmaceutical composition according to the invention with an antiemetic and / or antidiabetic agent for oral administration in the treatment of reshumania.

In a preferred embodiment of the invention, the pharmaceutical composition according to the invention is administered with an antiemetic and / or antidiabetic agent. Administration can be performed simultaneously or subsequently. Anti-emetic agents and anti-diarrheal agents may be administered independently of each other. The anti-emetic agent and / or anti-corrosive agent may be contained in the pharmaceutical composition according to the present invention or in an independent pharmaceutical formulation thereof.

Suitable antiemetic agents are, for example, 5-HT3-receptor antagonists, substituted benzamides, corticosteroids, antihistamines, phenothiatin type neuroleptics, butyrophenone type neuroleptics, benzodiazepines and cannabinoids. Preferred antiemetic agents are, inter alia, metoclopramide, domperidone and alizaprid.

Suitable antidiagnostic agents are, among others, opioids such as loperamide.

The solid oral pharmaceutical composition according to the invention is preferably useful for the treatment of leschmania. Other protozoan diseases that can be treated by the preparations according to the invention are, for example, malaria, tripanosomosis, toxoplasmosis, barbecosis, amebic dysentery and rambellosis. The preparations according to the invention are particularly suitable for diseases of pathogens present in organs such as liver, spleen or kidney, lymph nodules, bone marrow and blood.

The invention is further illustrated without limitation by the following examples.

Claims (23)

A flow-modifying agent selected from miltefosine and highly dispersible or colloidal silicon dioxide, magnesium stearate, talc, talc siliconisatum, calcium arachinate, cetyl alcohol, myristyl alcohol and mixtures thereof; One lubricant selected from magnesium stearate or calcium stearate, D, L-leucine, talc, stearic acid, lauric acid, polyglycol, fatty alcohols and waxes; Or both the flow-controlling agent and the lubricant; And one filler selected from lactose, glucose, fructose, calcium phosphate, calcium sulfate, calcium carbonate, starch, modified starch, sorbitol, mannitol, sugar alcohols, cellulose derivatives, saccharose, microcrystalline cellulose and mixtures thereof, Manufactured by physically mixing under the condition that the humidity of the manufacturing room is 40% or less, Miltefosine is orally administered over a period of 2 to 6 weeks with a total daily oral dose of 10 to 250 mg, A solid pharmaceutical composition for oral administration in the treatment of reshumania, comprising Miltefosine, the rheology-modulating agent, a lubricant or both, and the filler. The solid pharmaceutical composition of claim 1, wherein the solid composition is selected from the group consisting of capsules, tablets, effervescent tablets, effervescent blends and sachets (drinkable blends). The solid pharmaceutical composition according to claim 1 or 2, wherein the rheology-modulator is selected from the group consisting of silicon dioxide, talc, magnesium stearate and mixtures thereof. The solid pharmaceutical composition according to claim 1 or 2, wherein the filler is selected from the group consisting of cellulose, lactose, mannitol, calcium phosphate and mixtures thereof. The method according to claim 1 or 2, wherein the ratio of hexadecylphosphocholine (HPC) to the rheology-modifying agent, lubricant or both is 0.01 to 0.6 parts by weight of the rheology-modifying agent, lubricant or both per part by weight of HPC. Solid pharmaceutical composition characterized by. The solid pharmaceutical composition according to claim 1 or 2, wherein the ratio of hexadecylphosphocholine (HPC) to the filler is 0.1 to 120 parts by weight of the filler per 1 part by weight of HPC. delete The solid pharmaceutical composition according to claim 1 or 2, wherein the flowable composition obtained can be granulated prior to processing into tablets, capsules or sachets. The method of claim 1 or 2, further comprising: a disintegrant; Binders; Anti-adhesives selected from glycol, starch, talc, talc siliconisatum, aluminum stearate, stearic acid, magnesium stearate, calcium stearate or D, L-leucine; Gelatin, natural sugars, lecithin, pectin starch, cyclodextrin and cyclodextrin derivatives, polyvinyl pyrrolidone, polyvinyl acetate, gum arabic, alginic acid, tilose, talc, lycopodium, silica gel, cellulose, cellulose derivatives, fatty acids But also magnesium, calcium or aluminum salts of fatty acids having 12 to 22 carbon atoms, emulsifiers, fats and oils, mono-, di- and triglycerides of saturated fatty acids C ₁₂ H ₂₄ O ₂ to C ₁₈ H ₃₆ O ₂ and mixtures thereof , Aliphatic saturated or unsaturated fatty acids having pharmaceutically acceptable monohydric or polyhydric alcohols and polyglycols and derivatives thereof, monohydric aliphatic alcohols (1-20 carbon atoms) or polyhydric alcohols which may be unetherified or etherified ( Esters of 2 to 22 carbon atoms), esters of primary alcohols and citric acid, acetic acid, benzylbenzoate, dioxalane, glycerin Formal, tetrahydrofurfuryl alcohol, polyglycol ether with C ₁ -C ₁₂ alcohol, dimethylacetamide, lactamide, lactate, ethyl carbonate, silicon, calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, or magnesium carbonate Carrier selected from; Effervescent mixtures which are carbonate components and acid components; Solid pharmaceutical composition, characterized in that it may further comprise one or more excipients (adjuvant) selected from the group consisting of flavors, sweeteners and fragrances. (a) a flow-modifying agent selected from miltefosine and highly dispersible or colloidal silicon dioxide, magnesium stearate, talc, talc siliconistum, calcium arachinate, cetyl alcohol, myristyl alcohol and mixtures thereof; And one filler selected from lactose, glucose, fructose, calcium phosphate, calcium sulfate, calcium carbonate, starch, modified starch, sorbitol, mannitol, sugar alcohols, cellulose derivatives, saccharose, microcrystalline cellulose and mixtures thereof To obtain a flowable pharmaceutical composition, (b) filling the obtained mixture into capsules or sachets, or compressing the obtained mixture into tablets, to prepare a solid pharmaceutical composition according to claim 1. The process according to claim 10, wherein the flowable composition obtained according to step (a) can be granulated by known methods before step (b). delete The solid pharmaceutical composition according to claim 1, wherein the total daily dose is 50 to 150 mg of milteosin. The solid pharmaceutical composition according to claim 1 or 13, which is administered continuously daily for a period of 4 weeks. The solid pharmaceutical composition according to claim 1 or 13, wherein when the total daily dose is 50, 100 and 150 mg of miltefosine, it is orally administered once, twice or three times per day, respectively. 16. The solid pharmaceutical composition of claim 15, wherein a multiple daily dose is administered in the same amount by administering 100 mg / day at 2 × 50 mg / day or 150 mg / day at 3 × 50 mg / day. A method for treating reshumaniasis in non-human mammals by oral administration of 1-15 mg of Miltefosine per kg body weight of the mammal over a total of 2-8 weeks. 18. The method of claim 17, wherein the initial daily single dose (loading dose) is 3-15 mg / kg and the subsequent daily dose (maintenance dose) is 1-10 mg / kg. The method of claim 18, wherein the loading dose is 5 to 10 mg / kg. The method of claim 18, wherein the maintenance dose is 3 to 5 mg / kg. 21. The method of any one of claims 17-20, wherein the oral administration period is four weeks. 21. The method of any one of claims 17-20, wherein the small pet is treated including a dog, all rodents and hamsters. A pharmaceutical combination for the treatment of reshumania in a mammal, comprising the pharmaceutical composition according to claim 1 and an antiemetic agent, an antidiarrheal agent or both, which are administered together or independently of each other.